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Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

  • Chapter
Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 851))

Abstract

Cytochrome P450 3A4 (CYP3A4) is the major and most important drug-metabolizing enzyme in humans that oxidizes and clears over a half of all administered pharmaceuticals. This is possible because CYP3A4 is promiscuous with respect to substrate binding and has the ability to catalyze diverse oxidative chemistries in addition to traditional hydroxylation reactions. Furthermore, CYP3A4 binds and oxidizes a number of substrates in a cooperative manner and can be both induced and inactivated by drugs. In vivo, CYP3A4 inhibition could lead to undesired drug-drug interactions and drug toxicity, a major reason for late-stage clinical failures and withdrawal of marketed pharmaceuticals. Owing to its central role in drug metabolism, many aspects of CYP3A4 catalysis have been extensively studied by various techniques. Here, we give an overview of experimental and theoretical methods currently used for investigation and prediction of CYP3A4-ligand interactions, a defining factor in drug metabolism, with an emphasis on the problems addressed and conclusions derived from the studies.

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Notes

  1. 1.

    Abbreviations: ANF α-naphthoflavone, BEC bromoergocryptine, BFC 7-benzyloxy-4-trifluoromethylcoumarin, BQ 7-benzyloxyquinoline, b5 cytochrome b 5, CPR NADPH-cytochrome P450 oxidoreductase, CYP or P450 cytochrome P450.

  2. 2.

    A review of this scope cannot include all the references pertaining to the subject matter.

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Acknowledgments

Financial support from the National Institute of General Medical Sciences (Grant GM57353) and the California Center for Antiviral Drug Discovery is gratefully appreciated.

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, 92697, USA

    Irina F. Sevrioukova

  2. Departments of Molecular Biology and Biochemistry, Chemistry, and Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA

    Thomas L. Poulos

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  1. Irina F. Sevrioukova
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  2. Thomas L. Poulos
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Correspondence to Irina F. Sevrioukova .

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Editors and Affiliations

  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Eugene G. Hrycay

  2. Fac. of Pharmaceutical Sciences, The University of British Columbia , Vancouver, British Columbia, Canada

    Stelvio M. Bandiera

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Sevrioukova, I.F., Poulos, T.L. (2015). Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions. In: Hrycay, E., Bandiera, S. (eds) Monooxygenase, Peroxidase and Peroxygenase Properties and Mechanisms of Cytochrome P450. Advances in Experimental Medicine and Biology, vol 851. Springer, Cham. https://doi.org/10.1007/978-3-319-16009-2_3

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